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PNAS Papers Look at Remethylation in DNMT3A-Deficient Setting, Glioblastoma Glycans, More

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.

Washington University School of Medicine researchers report on findings from mouse experiments aimed at restoring activity by the DNA methyltransferase 3A enzyme-coding gene DNMT3A, which has been implicated in both acute myeloid leukemia (AML) initiation and age-related clonal hematopoiesis (ARCH). Using an inducible, transgenic version of the gene, the team used bisulfite sequencing and RNA sequencing to detect re-methylation in hematopoietic stem cells from mice that missing DNMT3A due to a prior bone marrow transplant, demonstrating that it could partially reverse gene expression shifts linked to DNMT3A mutations. These data show that "DNMT3A addback partially corrected dysregulated gene expression, and mitigated the expansion of myeloid cells," the authors report, noting that "this genetic proof-of-concept experiment suggests that this approach could be relevant for patients with ARCH or AML caused by loss-of-function DNMT3A mutations."

A team from the Netherlands, the US, and Argentina explore potential O-linked glycan signatures of immune response in glioblastoma (GBM). The researchers profiled glycan and receptor expression in patient-derived GBM samples, uncovering a rise in representation by truncated O-linked glycans and corresponding receptors in CD163+ tumor-associated macrophage and microglia immune cells. Their follow-up mass spectrometry experiments suggest that such O-linked glycans may influence PD-L1-positive macrophage infiltration and other immune features in mouse models of the aggressive brain cancer. "An improved understanding of the glioblastoma glycocode could lead to new prognostic and therapeutic clinical applications," they write.

Researchers from the Chinese Academy of Sciences and other centers in China take a closer look at the relationships between aging, lipid metabolism, and age-dependent DNA methylation in human cell line and mouse model experiments, focusing on the ELOVL fatty acid elongase 2 enzyme-coding gene Elovl2 — a contributor to polyunsaturated fatty acids (PUFA) synthesis that has been implicated in diabetes and age prediction in past analyses. "[W]e show that lack of Elov12 leads to a decline in PUFA synthesis and the accumulation of short fatty acids, including PUFA precursors in [the endoplasmic reticulum (ER)], altering mitochondrial energy metabolism and resulting in chronic ER stress and mitochondria dysfunction," they report, noting that these shifts "resulted in aging phenotypes, including stem cell exhaustion, cognitive decline, retinal degeneration, and glucose intolerance."